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Donald L Morton

Publications and source records attributed to Donald L Morton.

At least 37 records · Page 2Linked to original sources
PubMed2005

Therapeutic vaccines for melanoma: current status.

Considerable clinical research is focused on improving systemic treatments for melanoma. Unfortunately, the disease is generally resistant to standard chemotherapy, and surgical excision remains the best treatment option whenever possible. However, complete spontaneous regression of melanoma has been observed in some patients, a phenomenon thought to be mediated by the immune system. This has stimulated attempts to manipulate the immune system for therapeutic purposes. Vaccination is a form of active specific immunotherapy, such that the response against the tumor is actively generated by the patient's immune system, and is directed against a particular cellular target or specific membrane antigen. Numerous approaches to vaccination for melanoma have been investigated, and have become more complex as our understanding of anti-tumor immunity has increased. Vaccines have been shown to induce measurable immunologic responses that may be correlated with improved clinical outcomes in patients with melanoma. Large phase III clinical trials using peptide, ganglioside, and whole-cell tumor antigens are ongoing. Although anti-tumor vaccination has shown promising results in patients with melanoma, to date no vaccine has been approved for routine therapy of melanoma. Recently, a phase III trial evaluating the Canvaxin whole-cell vaccine in stage IV melanoma was halted because of a low likelihood of significant benefit. However, a larger phase III trial for patients with stage III disease was continued and results are awaited with interest.

Cancer Vaccines↗
PubMed2004

Gangliosides of organ-confined versus metastatic androgen-receptor-negative prostate cancer.

Prior development of a unique androgen-receptor (AR)-negative cell line (HH870) from organ-confined (T2b) human prostate cancer (CaP) enabled comparison of the gangliosides associated with normal and neoplastic prostate epithelial cells, organ-confined versus metastatic (DU 145, PC-3), and AR-negative versus AR-positive CaP cell lines. Resorcinol-HCl and specific monoclonal antibodies were used to characterize gangliosides on 2D-chromatograms, and to visualize them on the cell surface with confocal-fluorescence microscopy. AR-negative cells expressed GM1b, GM2, GD2, GD1a, and GM3. GM1a, GD1b, and GT1b were undetectable. GM1b and GD1a were more prominent in AR-negative than in AR-positive cells. PC-3 and HH870 cells were unique in the expression of O-acetylGD2 (O-AcGD2) and two alpha2,3-sialidase-resistant, alkali-susceptible GMR17-reactive gangliosides. Expression of GD1a, GM1b, doublets of GD3, GD2, and O-AcGD2, and the presence of an additional alkali-labile-14.G2a-reactive ganglioside, two alkali-susceptible, and three alkali-resistant GMR17-reactive gangliosides makes HH870 a potential component of a polyvalent-vaccine for active-specific immunotherapy of CaP.

Animals↗
PubMed2004

Peripheral blood CD4+ T-cell response before postoperative active immunotherapy correlates with clinical outcome in metastatic melanoma.

BACKGROUND: Canvaxin polyvalent specific active immunotherapeutic (CancerVax Corp., Carlsbad, CA) is a minimally toxic adjuvant after resection of regional metastatic melanoma. Because Canvaxin immunotherapeutic requires induction of an immune response, we hypothesized that survival would be directly correlated with cellular immune responses to Canvaxin cells prior to immunization. METHODS: We randomly selected 54 patients from a study of Canvaxin therapy after complete resection of American Joint Committee on Cancer (AJCC) stage III melanoma. Peripheral blood lymphocytes (PBLs) collected before immunotherapy were co-cultured with Canvaxin cells; cellular response was determined by flow cytometric measurement of the production of intracellular interleukin 4 (IL4) or interferon gamma (IFNgamma) by CD4(+) T-cells. Results were calculated as percent positive for double staining of CD4(+) plus IL4(+) or CD4(+) plus IFNgamma(+). RESULTS: The mean (+/- SD) increase in cytokine-producing CD4(+) T-cells after Canvaxin stimulation was 4.8 +/- 2.3% for an IFN response and 5.1 +/- 2.0% for an IL4 response. Both increases were significantly correlated with overall survival by univariate analysis (P = .0471 for IFNgamma and 0.002 for IL4). There was no significant correlation between unstimulated IFNgamma/IL4 responses and overall survival. Multivariate analysis showed that a CD4(+) T-cell IL4 response before Canvaxin therapy was a significant independent prognostic variable. CONCLUSIONS: In vitro cellular immune response to Canvaxin cells directly correlates with survival after subsequent initiation of immunotherapy for AJCC stage III melanoma. This finding will be evaluated in a multicenter phase III trial of Canvaxin plus bacille Calmette-Guerin (BCG) versus placebo plus BCG after resection of stage III melanoma.

Aged↗
PubMed2004

Tumor-microenvironment interactions: the fucose-generating FX enzyme controls adhesive properties of colorectal cancer cells.

Extravasation of tumor cells is a pivotal step in metastasis formation. This step is initiated by an interaction of extravasating tumor cells with endothelial cells. Among the molecules mediating tumor-endothelium interactions are selectins and their fucosylated ligands. In a previous study, we demonstrated that the fucose-generating FX enzyme regulates the expression of selectin ligands by B and T lymphocytes and by head and neck squamous cell carcinoma cells. It was also shown that the FX enzyme regulated important interaction parameters between these cancer cells and endothelial cells. The present study was aimed to determine whether the FX enzyme controls adhesive interactions between colorectal cancer cells and endothelial cells. The results clearly indicate that this is indeed the case. Overexpressing the FX enzyme by the transfer of FX cDNA to low FX-expressing colorectal cancer cells resulted in an increased adhesive capacity of the transfectants to activated endothelial cells and to recombinant E-selectin. Down-regulating FX levels in colorectal cancer cells expressing high levels of endogenous FX by transfection with small-interfering RNA resulted in a down-regulated expression of the selectin ligand sialyl Lewis-a and a decrease in the adhesive capacity of the transfectants to activated endothelial cells and to recombinant E-selectin. These transfection experiments also indicated that manipulating the levels of the FX enzyme affected global cellular fucosylation and altered the interaction of colorectal cancer cells with some extracellular matrix components such as fibronectin. We also found that highly metastatic colorectal cancer variants express higher levels of FX and of sialyl Lewis-a than low metastatic variants originating in the same tumors. These results lead us to hypothesize that the FX enzyme controls the capacity of colorectal cancer to extravasate and form metastasis. If this hypothesis will be confirmed the FX enzyme could become a target molecule for metastasis prevention.

CA-19-9 Antigen↗
PubMed2004

Factors predictive of tumor-positive nonsentinel lymph nodes after tumor-positive sentinel lymph node dissection for melanoma.

PURPOSE: Approximately 20% of sentinel node (SN) positive melanoma patients have additional non-SN (NSN) metastasis. The rationale for this study was to identify the factors associated with additional nodal disease, as a method to determine which patients may most benefit from completion lymph node dissection (CLND). PATIENTS AND METHODS: During 1990 to 2002, 1,599 patients have undergone SN biopsy at our institute. 19.5% underwent CLND for tumor-positive SN. One hundred ninety-one of these patients had clinicopathologic information available for review. Univariate analyses used chi2 test, Wilcoxson rank sum test, and chi2 test for trend. Multivariate analyses used logistic regression and Wald test. RESULTS: Forty-six (24%) patients had tumor-positive NSN. Univariate analyses showed that primary thickness (Breslow and Clark), primary site, SN tumor size, and number of tumor-positive SNs were significantly associated with tumor-positive NSN. Multivariate analysis (167 patients), confirmed that Breslow and SN tumor size were independently predictive. Sex, histology, ulceration, mitotic index, and SN basin location were not predictive. Risk stratification by the number of prognostic factors present (Breslow > or = 3 mm and SN tumor size > or = 2 mm) showed that probability of finding tumor-positive NSN was 12.3% in the low-risk group (0 factors), 30.9% in the intermediate-risk group (1 factor), and 41.9% in the high-risk group (2 factors). CONCLUSION: Thicker primary and larger SN tumor size are factors that correlate best with tumor-positive NSN. Although none of these factors are absolutely predictive of residual nodal disease, these factors must be strongly considered if the SN contains metastasis, as they provide enhanced risk assessment for NSN tumor-positivity.

Adolescent↗
PubMed2004

Prognostic significance of molecular upstaging of paraffin-embedded sentinel lymph nodes in melanoma patients.

PURPOSE: Detection of micrometastases in sentinel lymph nodes (SLNs) is important for accurate staging and prognosis in melanoma patients. However, a significant number of patients with histopathology-negative SLNs subsequently develop recurrent disease. We hypothesized that a quantitative realtime reverse transcriptase polymerase chain reaction (qRT) assay using multiple specific mRNA markers could detect occult metastasis in paraffin-embedded (PE) SLNs to upstage and predict disease outcome. PATIENTS AND METHODS: qRT was performed on retrospectively collected PE SLNs from 215 clinically node-negative patients who underwent lymphatic mapping and sentinel lymphadenectomy for melanoma and were followed up for at least 8 years. PE SLNs (n = 308) from these patients were sectioned and assessed by qRT for mRNA of four melanoma-associated genes: MART-1 (antigen recognized by T cells-1), MAGE-A3 (melanoma antigen gene-A3 family), GalNAc-T (beta1-->4-N-acetylgalactosaminyl-transferase), and Pax3 (paired-box homeotic gene transcription factor 3). RESULTS: Fifty-three (25%) patients had histopathology-positive SLNs by hemotoxylin and eosin and/or immunohistochemistry. Of the 162 patients with histopathology-negative SLNs, 48 (30%) had nodes that expressed at least one of the four qRT markers, and these 48 patients also had a significantly increased risk of disease recurrence by a Cox proportional hazards model analysis (P <.0001; risk ratio, 7.48; 95% CI, 3.70 to 15.15). The presence of > or = one marker in histopathology-negative SLNs was also a significant independent prognostic factor by multivariate analysis for overall survival (P =.0002; risk ratio, 11.42; 95% CI, 3.17 to 41.1). CONCLUSION: Molecular upstaging of PE histopathology-negative SLNs by multiple-marker qRT assay is a significant independent prognostic factor for long-term disease recurrence and overall survival of patients with early-stage melanoma.

Adult↗
PubMed2004

Profiling epigenetic inactivation of tumor suppressor genes in tumors and plasma from cutaneous melanoma patients.

Aberrant methylation of CpG islands in promoter regions of tumor suppressor genes (TSG) has been demonstrated in epithelial origin tumors. However, the methylation profiling of tumor-related gene promoter regions in cutaneous melanoma tumors has not been reported. Seven known or candidate TSGs that are frequently hypermethylated in carcinomas were assessed by methylation-specific polymerase chain reaction (MSP) in 15 melanoma cell lines and 130 cutaneous melanoma tumors. Four TSGs were frequently hypermethylated in 86 metastatic tumor specimens: retinoic acid receptor-beta2 (RAR-beta2) (70%), RAS association domain family protein 1A (RASSF1A) (57%), and O6-methylguanine DNA methylatransferase (MGMT) (34%), and death-associated protein kinase (DAPK) (19%). Hypermethylation of MGMT, RASSF1A, and DAPK was significantly lower in primary melanomas (n=20) compared to metastatic melanomas. However, hypermethylation of RAR-beta2 was 70% in both primary and metastatic melanomas. Cell lines had hypermethylation profiles similar to those of metastatic melanomas. The analysis of these four markers of metastatic tumors demonstrated that 97% had > or =1 gene(s) and 59% had > or =2 genes hypermethylated. The methylation of genes was verified by bisulfite sequencing. The mRNA transcripts could be re-expressed in melanoma cell lines having hypermethylated genes following treatment with 5'-aza 2'-deoxycytidine (5Aza-dC). Analysis of melanoma patients' plasma (preoperative blood; n=31) demonstrated circulating hypermethylated MGMT, RAR-beta2, and RASSF1A DNA for at least one of the markers in 29% of the patients. Our findings indicate that the incidence of TSG hypermethylation increases during tumor progression. Methylation of TSG may play a significant role in cutaneous melanoma progression.

DNA↗
PubMed2004

Allelic imbalance of 12q22-23 associated with APAF-1 locus correlates with poor disease outcome in cutaneous melanoma.

Cutaneous melanoma is a highly aggressive tumor that is relatively resistant to chemotherapy and radiotherapy. This resistance may be in part due to inhibition of apoptosis. Apoptotic protease activating factor-1(APAF-1), a candidate tumor suppressor gene, mediates p53-induced apoptosis, and its loss promotes oncogenic transformation. To determine whether loss of the APAF-1 locus influences tumor progression, we assessed loss of heterozygosity microsatellites on the APAF-1 locus (12q22-23) in 62 primary and 112 metastatic melanomas. We discovered that frequency of allelic imbalance was significantly higher in metastatic tumors (n = 36 of 98; 37%) than in primary melanomas (n = 10 of 54; 19%; P = 0.02). In metastatic melanomas, APAF-1 loss significantly correlated with a worse prognosis (P < 0.05) in the patients, and its loss during melanoma tumor progression suggests that APAF-1 is a tumor suppressor gene. Furthermore, loss of heterozygosity was frequent in the 12q22-23 chromosome region centromeric to the APAF-1 locus suggesting that other tumor-related genes may be present in the 12q22-23 region. In summary, the study demonstrates that allelic imbalance in the 12q22-23 region is a genomic surrogate of poor disease outcome for cutaneous melanoma patients.

Apoptosis↗
PubMed2004

Incidence of BRAF oncogene mutation and clinical relevance for primary cutaneous melanomas.

PURPOSE: The purpose of the study was to clarify the incidence of B-raf oncogene (BRAF) mutations in primary cutaneous melanomas, their relation to tumor progression, and effect on disease outcome. Somatic mutations of BRAF kinase, a component of the Ras-mitogen-activated protein/extracellular signal-regulated kinase kinase-mitogen-activated protein kinase pathway, are frequently reported (>65%) in nevi and malignant melanomas. EXPERIMENTAL DESIGN: We assessed BRAF mutation frequency in exons 11 and 15 in primary (n = 59) and metastatic (n = 68) melanomas. Direct sequencing of PCR products was performed on DNA isolated and purified from microdissected tumors. RESULTS: Eighteen mutations (31%) at exon 15 were detected in primary melanoma with a significantly (P = 0.001) higher frequency in patients < 60 years old. Incidence of BRAF mutation did not correlate with Breslow thickness. Presence of BRAF mutation of primary tumors did not effect overall disease-free survival. BRAF mutation frequency in metastatic lesions was 57% and significantly (P = 0.0024) higher than primary melanomas. CONCLUSIONS: The study suggests that BRAF mutation may be acquired during development of metastasis but is not a significant factor for primary tumor development and disease outcome.

Aged↗
PubMed2004

Prolonged survival after complete resection of metastases from intraocular melanoma.

BACKGROUND: The median survival time is only 2-6 months after a diagnosis of metastases from intraocular melanoma. Because complete resection of metastatic melanoma from a cutaneous primary tumor can prolong survival, the authors hypothesized that resection also might benefit patients with metastases from an intraocular site. METHODS: From 1971 to 1999, 112 patients with metastatic melanoma from an intraocular site were enrolled in various treatment protocols after informed consent was obtained. Prospectively recorded clinical variables and follow-up information were retrieved from the patient database. Survival curves were estimated using the Kaplan-Meier method. Univariate analysis was performed with the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model. Propensity score analysis was used to reduce the imbalance between subgroups and to assess treatment effect. RESULTS: Seventy-eight patients (70%) presented with liver involvement. Twenty-four patients (21%) underwent resection of metastatic lesions. At a median follow-up time of 11 months (range, 1-97 months; > 36 months for survivors), the median survival period was 11 months and the 5-year survival rate was 7%. Univariate analysis showed that surgical resection, site of metastases, number of metastatic lesions, and disease-free interval were correlated significantly with survival (P < 0.001, P < 0.001, P < 0.001, and P = 0.031, respectively). Multivariate analysis showed that surgical resection was significant (P = 0.008) but that the site of metastases was not (P = 0.146). The median survival and the 5-year survival rate were 38 months and 39%, respectively, for surgical patients, versus 9 months and 0%, respectively, for nonsurgical patients. After adjusting for covariate imbalance by propensity score analysis, surgery remained significant (P = 0.021) on multivariate analysis. CONCLUSIONS: Complete resection may prolong survival in certain patients with distant metastases from intraocular primary melanoma. However, the overall unfavorable prognosis indicates an urgent need for more effective nonsurgical interventions.

Aged↗
PubMed2004

Lymphatic mapping and sentinel lymphadenectomy for primary and metastatic pulmonary malignant neoplasms.

BACKGROUND: Mediastinal lymph node sampling understages a significant number of lung cancers, even when nodes are evaluated by immunohistochemical techniques. Intraoperative lymphatic mapping and sentinel lymphadenectomy allows focused pathologic evaluation of a few lymph nodes that accurately stage the entire basin. HYPOTHESIS: Lymphatic mapping and sentinel lymphadenectomy is a practical and accurate method of staging lymph nodes that drain primary and metastatic neoplasms of the lung. DESIGN AND SETTING: Retrospective review at a tertiary referral center. PATIENTS: Sixty-seven patients undergoing resection of lung tumors. MAIN OUTCOME MEASURES: Sentinel lymph node (SN) identification rate, number of SNs, nodal pathologic features, and survival. RESULTS: Twenty-eight patients had primary lung cancer and 39 had pulmonary metastases from melanoma (33 cases), squamous cell carcinoma (2 cases), colon cancer (2 cases), or other cancers (2 cases). Lymphatic mapping and sentinel lymphadenectomy was successful in all patients. The median number of lymph nodes identified by dye alone was 2 (range, 1-7); the median number identified by dye plus radiocolloid was 4 (range, 1-9). Most SNs (69%) were N1; 31% were N2. Lower lobe lesions drained to upper mediastinal nodes in 3 (13%) of 24 cases. Lymph node metastases were found in 11 patients with lung cancer (39%) and 8 patients with pulmonary metastases (21%). Ten (91%) of the 11 patients with lung cancer had SN involvement. In the 33 patients with metastatic melanoma, SN involvement significantly reduced the rate of 2-year survival (0% vs 48%). CONCLUSIONS: Lymphatic mapping and sentinel lymphadenectomy of intrapulmonary malignancies is technically challenging but feasible. Blue dye is most useful for in vivo identification of SNs; ex vivo radioactivity can confirm that excised nodes are SNs. Lymphatic mapping and sentinel lymphadenectomy can provide important prognostic information for patients with melanoma and lung metastases, and it may improve the staging of primary lung cancer.

Adult↗
PubMed2004

Contemporary surgical treatment of advanced-stage melanoma.

HYPOTHESIS: The clinical treatment of patients with stage IV melanoma according to criteria of the American Joint Committee on Cancer (AJCC) is controversial because the 5-year survival rate is approximately 5%. Specific clinicopathologic factors are predictive of survival following curative surgery. DESIGN: Cohort analysis of 1574 successive patients undergoing surgical resection of metastatic melanoma for a 29-year period. Patients received follow-up on a routine basis with serial examinations and radiographic studies. The median follow-up time was 19 months (range, 1-382 months). SETTING: Tertiary cancer center. PATIENTS: Surgical resection was performed in 1574 patients. The decision to perform surgery was individualized for each patient. INTERVENTION: The technique of surgical resection was based on the site of metastasis. Main Outcome Measure Computer-assisted database with statistical analyses using log-rank tests and Cox regression models. RESULTS: Of the 4426 patients with AJCC stage IV melanoma, 1574 (35%) underwent surgical resection; 970 (62%) were men, with a median age of 50 years. Of the primary melanomas, 46% arose on the trunk, and 56% were Clark level IV or V with a median thickness of 2.2 mm. We found 697 patients (44%) to have AJCC stage III melanoma (lymph node) prior to the development of stage IV metastases. The most common site for resection was the lung (42%), followed by the skin or lymph node (19%) and the alimentary tract (16%). Of our patients, 877 (56%) had melanoma at a single site. The 5-year survival rate was significantly (P<.001) better for patients with a solitary melanoma (mean +/- SD, 29% +/- 2%) than those with 4 or more metastases (n = 147; mean +/- SD, 11% +/- 3%). Skin and lymph node metastases had the most favorable survival rate (median, 35.1 months). Multivariate analyses identified an earlier primary tumor stage (I vs II) (P<.001), an absence of intervening stage III metastases (P =.02), solitary metastasis (P<.001), and a long (>36 months) disease-free interval from AJCC stage I or II to stage IV (P =.005) as predictive of survival. CONCLUSIONS: Our results demonstrate the benefit of surgical resection for advanced-stage melanoma. Patients with limited sites and numbers of metastases should be considered for curative resection regardless of the location of the disease.

Adult↗
PubMed2004

Melanoma-inhibiting activity assay predicts survival in patients receiving a therapeutic cancer vaccine after complete resection of American Joint Committee on Cancer Stage III Melanoma.

BACKGROUND: More than half of melanoma patients rendered disease free by lymph node dissection will experience disease recurrence. We hypothesized that serum levels of melanoma-inhibiting activity (MIA) protein might be useful to stratify risk and identify subclinical recurrence in patients undergoing adjuvant immunotherapy. We examined MIA levels in the serum of stage III patients treated after surgery with a therapeutic cancer vaccine. METHODS: Three cohorts of 25 patients were randomly selected from our melanoma database on the basis of time to death (group 1, <1 year; group 2, 1-5 years; group 3, >5 years.) Prospectively collected serum samples were assayed in a blinded fashion for MIA by enzyme-linked immunosorbent assay. RESULTS: MIA was increased at any time in 19 (76%) of 25, 4 (16%) of 25, and 1 (4%) of 25 patients in groups 1, 2, and 3, respectively. The median survival was 11 months for the 25 patients with increased MIA and >75 months for the 50 patients with normal MIA. MIA increased above normal a median of 1 month (mean, 75 days) before clinical recurrence. All patients with increased MIA after 2 months of treatment subsequently died of melanoma. One patient in whom initially increased levels decreased to normal within 2 months is disease free. CONCLUSIONS: Serum MIA levels provide important prognostic information early in the course of stage III melanoma and often detect melanoma recurrences before clinical evidence of disease.

Cancer Vaccines↗
PubMed2004

Endogenous immune response to early- and intermediate-stage melanoma is correlated with outcomes and is independent of locoregional relapse and standard prognostic factors.

BACKGROUND: Standard prognostic factors, including precise staging of the regional lymph nodes, cannot accurately determine which early-stage melanomas will metastasize. The immune response to a 90-kd tumor-associated antigen correlates with occult nodal disease and survival of patients receiving vaccine therapy for melanoma. We hypothesized that this response might have prognostic significance independent of standard prognostic features. STUDY DESIGN: Patients with primary melanomas 1.01 to 2.00 mm and tumor-negative regional lymph nodes were identified. Group 1 comprised 50 patients who died of metastases within 7 years after complete surgical treatment; group 2 comprised 50 patients who were matched with group 1 for six standard prognostic features but who lived at least 10 years without recurrence. Postoperative sera were analyzed for an immune complex to TA90 and for immunoglobulin-G and immunoglobulin-M antibodies against TA90. RESULTS: Median thickness of the primary melanoma was 1.40 +/- 0.31 mm and 1.42 +/- 0.32 mm in groups 1 and 2, respectively; median Clark's level of invasion was III in both groups, and 26 patients in each group had ulcerated primaries. Median TA90-IC level and rate of TA90-IC positivity (optical density greater than 0.410) were 0.557 +/- 0.43 and 82%, respectively, in group 1 and 0.305 +/- 0.15 and 18%, respectively, in group 2 (p < 0.001). The anti-TA90 IgM level was significantly elevated in 12% of group 1 (median titer 1:150) and 62% of group 2 (median titer 1:800) (p < 0.001). There was no significant difference in anti-TA90 IgG levels between the two groups. CONCLUSIONS: A positive TA90-IC level and absence of an anti-TA90 IgM response correlate with distant metastasis when melanoma is low risk or intermediate risk by standard prognostic factors.

Adult↗
PubMed2004

Prediction of metastatic melanoma in nonsentinel nodes and clinical outcome based on the primary melanoma and the sentinel node.

Lymphatic mapping and sentinel node biopsy are well-established techniques for staging and managing patients with melanoma, breast cancer and other malignancies that spread initially to the regional lymph nodes. Identification of tumor in the sentinel node is the most precise staging technique currently available. The sentinel node is the site of metastatic melanoma in approximately 20% of melanoma patients and if tumor is present in the sentinel node it is customary to perform a complete dissection of the lymph nodes of the affected nodal basin. This may be overtreatment for some patients as tumor is identified in the nonsentinel nodes of only one-third of sentinel node-positive melanoma patients treated by completion lymphadenectomy. If it were possible accurately to identify the minority of patients with tumor in the nonsentinel nodes, the patients most likely to benefit from lymphadenectomy, the remaining patients could be spared a potentially morbid operation that is unlikely to confer clinical advantage. In 90 patients with a melanoma-positive sentinel node, who subsequently had a completion lymphadenectomy, we evaluated and compared the capacity of characteristics of the primary melanoma and of the sentinel node to predict individuals likely to have tumor in nonsentinel nodes. We assessed the Breslow thickness of the primary, the amount of tumor in the sentinel node (relative tumor area) and, as an index of immune modulation of the sentinel node, the density of dendritic leukocytes in the nodal paracortex. The relative area of tumor in the sentinel node and Breslow thickness of the primary melanoma most accurately predicted the presence of tumor in the nonsentinel nodes (P=0.0001 in both cases-Wilcoxon rank sums). The presence of melanoma in the nonsentinel nodes was also predicted by the density of dendritic leukocytes in the paracortex (P=0.008-Wilcoxon rank sums). These three observations assessed alone and in combination predict the presence of tumor in the nonsentinel nodes with high accuracy. The same characteristics also significantly correlated with tumor recurrence (tumor burden, P=0.0001, Breslow, P=0.0001 and dendritic cell density, P=0.0007) and death from melanoma (tumor burden, P=0.0001, Breslow, P=0.0001 and dendritic cell density, P=0.0026).

Antigens, Neoplasm↗
PubMed2004

Detection of differentially expressed proteins in early-stage melanoma patients using SELDI-TOF mass spectrometry.

Tumor progression is a dynamic sequence of events that involves specific protein changes. We hypothesized that Surface Enhanced Laser Desorption/Ionization (SELDI) mass spectrometric analysis of sera from patients with AJCC stage I and II melanoma with negative loco-regional lymph nodes could identify potential melanoma-associated protein biomarkers of disease recurrence. Serum specimens were collected from 49 patients who developed recurrence (n = 25) or remained free of recurrence (n = 24) without evidence of disease following complete resection (AJCC stage I and II). Follow-up was longer than 5 years. Serum proteins were denatured and applied onto two protein chip chemistry surfaces (weak cationic WCX2; metal-binding, IMAC3-Cu). SELDI ProteinChip mass spectrometry was then performed. SELDI data were analyzed, protein peak clustering and classification were performed, and a supervised classification algorithm was employed to classify the dataset. Multiple protein peaks ranging from 3.3 to 30 kDa were identified between patients with recurrence and those without recurrence, and the expression pattern differences of three proteins were used to generate the discriminating classification tree. The biomarkers were expressed with a high degree of reproducibility. In this early characterization study, melanoma recurrence was predicted with a sensitivity of 72% (18/25) and a specificity of 75% (18/24). This novel pilot study revealed three proteins that accurately identified patients who developed recurrence after curative resection of primary melanoma.

Adult↗
PubMed2003

Phase I pilot clinical trial of human IgM monoclonal antibody to ganglioside GM3 in patients with metastatic melanoma.

PURPOSE: A human monoclonal antibody (L612 HuMAb) that binds to ganglioside GM3 has been developed in our laboratory. L612 HuMAb is a 100% human IgM protein. L612 HuMAb binds to cell surface of melanoma and can kill the cells in the presence of complement. The primary objective of this study was to test the toxicity and pharmacokinetics associated with administration of L612 HuMAb to melanoma patients whose tumor cells expressed GM3. EXPERIMENTAL DESIGN: Nine patients with measurable metastatic melanoma (American Joint Committee on Cancer stage IV) were entered in the study. Eight had failed previous treatments that included chemotherapy, radiation therapy, melanoma cell vaccine, and/or biological therapy. All patients received a 48-h continuous infusion of L612 HuMAb at a dose of 960 mg, 1,440 mg, or 1,920 mg. Five of these patients received a second infusion and one patient received a third infusion, all with the previous dose. RESULTS: Toxicity was limited to transient and mild pruritus and skin rash. One patient complained of pain at the site of subcutaneous metastases. Serum antibody levels peaked 24 to 48 h after starting the infusion. Two patients, one receiving a single course of 960 mg (612 mg/m(2)) and the second receiving two courses of 1,440 mg (911 mg/m(2)) followed by surgical therapy, are without evidence of disease >5 years after antibody infusion. CONCLUSIONS: The human IgM monoclonal antibody, L612 HuMAb, was well tolerated. Infusion of L612 HuMAb appears to produce significant antitumor activity in melanoma patients.

Adult↗